The present study demonstrates that CD4 ؉ CD25 ؉ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4 ؉ CD25 ؉ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 ( IntroductionHIV infection is mainly associated with a progressive decrease in the number of CD4 ϩ T lymphocytes and defective CD4-specific and CD8-specific T-cell responses against HIV and other pathogens. It has been demonstrated that highly active antiretroviral therapy (HAART) results in reduced HIV-1 replication, increased CD4 cell counts in most treated patients, and progressive but incomplete recovery of CD4 ϩ T-cell functions. [1][2][3][4] Thus, treatment of chronic HIV infection does not result in most cases in a full recovery of HIV-specific helper and cytotoxic T lymphocyte (CTL) responses (reviewed in Sakaguchi et al 5 ).Recently, a CD4 ϩ T-cell subset with regulatory properties has been characterized in humans several years after their discovery in mice. [6][7][8][9][10] These cells, named "regulatory T" (Treg) cells express the ␣ chain of the interleukin 2 (IL-2) receptor (CD25) and can inhibit the proliferation of CD4 ϩ and CD8 ϩ T lymphocytes both in vitro and in vivo. 9,11 It has been demonstrated that transfer of such cells can protect neonatally thymectomized mice from autoimmune diseases, whereas their depletion results in the development of systemic autoimmune diseases. [12][13][14] Moreover, alloantigen-induced CD4 ϩ CD25 ϩ regulatory T cells were reported to prevent rejection initiated by CD4 ϩ cells in both organ and bone marrow transplantation. 15,16 Although CD25 is usually considered as an activation marker, it has been shown that CD4 ϩ CD25 ϩ lymphocytes do not proliferate in response to polyclonal, allogenic, or antigen-specific stimulation 8,9,17 but require activation through their T-cell receptor (TCR) to exert their suppressive function. Their anergic state could be partially reversed by IL-2 and IL-15. 9 Besides CD4 ϩ CD25 ϩ regulatory T cells, 2 other types of CD4 ϩ cells with suppressive function have been described: type 1 T regulatory (Tr1) cells 18 and T-helper 3 (Th3) cells. 19 Tr1 cells were reported to suppress the immune response via the secretion of the immunosuppressive cytokines IL-10 and transforming growth factor ␤ (TGF-␤). The mechanism by which CD4 ϩ CD25 ϩ T cells mediate suppression seems to require direct cell-cell contact. Levings et al 19 have recently demonstrated, at the clonal level, that Tr1 and CD4 ϩ CD25 ϩ T cells are distinct subsets of regulatory T cells and that the suppression mediated by CD4 ϩ CD25 ϩ T cells is partially dependent on TGF-␤.In healthy individuals, the CD4 ϩ CD25 ϩ T-cell subset represents 5% to 10% of peripheral CD4 ϩ T cells and is characterized by the constitutive expression of CD152 (CTL-associate...

Normal immunoglobulin G for therapeutic use (intravenous immunoglobulin [IVIg]) is used in an increasing number of immune-mediated conditions, including acute and chronic/relapsing autoimmune diseases, transplantation, and systemic inflammatory disorders. Several mutually nonexclusive mechanisms of action account for the immunoregulatory effects of IVIg. Although IVIg inhibits T-cell proliferation and T-cell cytokine production, it is unclear whether these effects are directly dependent on the effects of IVIg on T cells or they are dependent through the inhibition of antigen-presenting cell activity. Here, we examined the effects of IVIg on differentiation, maturation, and function of dendritic cells (DCs). We show that IVIg inhibits the differentiation and maturation of DCs in vitro and abrogates the capacity of mature DC to secrete interleukin-12 (IL-12) on activation while enhancing IL-10 production. IVIg-induced down-regulation of costimulatory molecules associated with modulation of cytokine secretion resulted in the inhibition of autoreactive and alloreactive T-cell activation and proliferation. Modulation of DC maturation and function by IVIg is of potential relevance to its immunomodulatory effects in controlling specific immune responses in autoimmune diseases, transplantation, and other immune-mediated conditions.